G-ethylmethylamino-s



United States Patent 6-ETHYLMETHYLAMINO-5-METHYL-4,4- DIPHENYL-HEXAN-3 ONE Eric Walton, London, England, assignor to Burroughs Wellcome & Co. (U. S. A.) Inc., Tuckahoe, N. Y., a corporation of New York No Drawing. Application January 29, 1952, Serial No. 268,907

Claims priority, application Great Britain February 12, 1951 3 Claims. (Cl. 260 570.?!)

Q on. CH:

' CH O COCIHI is known to have analgesic activity. Various analogs of this compound are also known and their analgesic activity, compared with amidone itself is discussed in Nature, volume 159, page 679, dated May 17, 1947, where it is shown that these known analogs are of poor analgesic activity. It was subsequently reported that l-amidone has about twice the activity of morphine (Nature, volume 160, page 65, dated November 1, 1947).

Various other compounds of this general type have been prepared and while some possess advantages at least as regards specific test animals, none has hitherto been found generally superior to amidone. As a rule the reaction sequence leading to the formation of compounds of the amidone type results in mixture of two isomers, I and II.

CH1 CH1 CH1.HNRg H-CHQNRZ a tDz 0 01 C O C H; C D 01K; I II Mixtures can be avoided either before the last step of the reaction sequence (addition of EtMgBr to the appropriate nitrile) by separation of the isomeric nitriles, or, after the reaction, through the fact that the ketimides corresponding to type II, are less rapidly hydrolyzed than those corresponding to type I.

It has now been found that the compounds 6-ethylmethylamino-S-methyl-4,4-diphenylhexan-3-one (Formula III) and 6 ethylmethylamino-4,4-diphenylheptan-3-one (Formula IV) or salts thereof such as the hydrobromide, hydriodide etc. also exhibit valuable analgesic properties comparable to those of amidone but with less marked concomitant side eifects.

This freedom from side effects is especially notable in dogs. It is well known that amidone" produces nausea, vomiting and other digestive disturbances in dogs in the dose range required for analgesia. The compounds of the present invention do not produce such effects, although their analgesic potency is at least equal to that Patented Feb. 21, 1956 of amidone, and therefore, are of value in veterinary medicine.

CH; CH1 CH3 CH3 Ph:|.C.CH.CHzN Ph:.C.CH:.( /'HN COEt C2115 OEt 02H;

III III The present invention therefore comprises, as pharmaceutical substances exhibiting improved analgesic properties, the compounds '6wethylmethylamino-5-methyl- 4,4-diphenylhexan-3-one and 6-ethylmethylamino-4,4-diphenylheptan-3-one. These compounds may be produced by any suitable synthetic routes.

The compounds of the present invention may be presented as salts with such acids as are not toxic at the dose level at which the compound is to be ad ministered.

The following examples illustrate the invention;

All temperatures are given in degrees centigrade.

EXAMPLE 1 Preparation of 6 ethylmethylamino 5 methyl-4,4-diphenylhexan-3-0ne Ethylmethylamine (160 g.), boiling point 34-36", and B-propylene oxide (160 g.) were heated in a closed vessel at 140 for 2 hours. After 16 hours the product was distilled and the fraction boiling at 140-144 collected; this consisted of l-ethylmethylamino-Z-propanol. The later (300 g.) dissolved in dry chloroform (250 ml.) was slowly added to a stirred solution of thionyl chloride (218 ml.) in more chloroform (900 ml.). After 24 hours at room temperature the chloroform and hydrogen chloride were removed in vacuo and the residue treated with excess dilute alkali and extracted with ether. The dried ethereal extract on distillation yielded l-ethylmethylamino- 2-chloropropane as an oil, boiling point 35-38/ 22 mm. (yield 268 g.).

The whole of this base was added over 1 hour to a stirred solution of diphenylmethylcyanide (422 g.) in dry benzene (1500 ml.) under gentle reflux and containing sodamide (99 g.) in suspension. After refluxing for a further 2 hours the product was decomposed with water and the benzene and ether extracts shaken with dilute hydrochloric acid. The acid layer with alkali gave a basic oil which on extraction with ether and distillation yielded a fraction (408 g.) boiling point -l50/.01 mm. consisting mainly of a mixture of S-ethylmethylamino-1,1-diphenylbutyl and 3-ethylmethyl-2-methyl-1,1- diphenylpropyl cyanides.

This mixture of bases was dissolved in dilute hydrochloric acid, washed with ether to remove traces of nonbasic oil, and evaporated to dryness. The residue dissolved in alcohol-ether gave early crops, which on recrystallization from the same solvent afforded pure hydrochloride of 3-ethylmethylamino-Z-methyl-1,1-diphenylpropyl cyanide, melting point 222-224.

In order to isolate the isomeric cyanide in pure form, the oily base, obtained from the hydrochloride mother liquor by treatment with alkali, was converted to the hydrobromide (as described above for the hydrochloride). The hydrobromide, on crystallization from alcohol, gave pure 3-ethylmethylamino-1,1-diphenylbutyl cyanide hydrobromide, melting point ISO-.

3 ethylmethylamino-Z-methyl-1,1-diphenylpropyl cyanide (10 g.) (from its hydrochloride) in dry ether was added to an ethereal solution of ethyl-magnesium bromide prepared from magnesium (2.5 g.) and ethylbromide (7.8 ml.). Dry xylene (50 ml.) was added, and after removal of the ether by evaporation the mixture was refluxed for 5 hours, whereupon a brownish-green adduct slowly separated. The product was decomposed with alkali (yellow to indigo-carmine), evaporated to dryness and extracted with ether. The ethereal extract was shaken with dilute hydrobromic acid and the acid extract refluxed for 2 hours, washed with ether and then evaporated to dryness. As the residue failed to give a crystalline hydrobromide it was converted to base, which was distilled at 135-146/.05 mm. This distillate with oxalic acid gave the acid oxalate of 6-ethylmethylamino-5-methyl-4,4-hexan-3-one, which crystallized from alcohol in hexagonal prisms, melting point 179-182; and with hydriodic acid, the hydriodide of the same ketone, which crystallized from alcohol-ether in needles, melting point 199-202.

EXAMPLE 2 Preparation of 6 ethylmethylaminc-4,4-diphenylheptan- 3-0ne 3-ethylmethylamino-1,l-diphenylbutyl cyanide (from its hydrobromide) (146 g.) in dry ether was added to an ethereal solution of ethylmagnesinm bromide prepared from magnesium (36.4 g.) and ethyl bromide (114 ml.). Dry xylene (250 ml.) was then added and the ether allowed to evaporate. The mixture was refluxed for 7 hours, during which time the adduct slowly separated. The product was decomposed with alkali (yellow to indigo-carmine), evaporated to dryness and Well extracted with ether. The ethereal extract was shaken with dilute hydrobromic acid and the acid extract boiled for hours, washed with ether and evaporated to dryness in vacuo.

Treatment of this residue with water gave a small amount of 6-ethylrnethylarninc-4,4-diphenylheptan-3-one hydrobromide, which on further crystallization from water formed tablets, melting point 193195, but most of the ketone was isolated as follows:

2. 6-ethylmethylarnino'4,4diphenylheptan-3-one. 3. A nontoxic acid-addition salt of 6-ethylrnethylamino- 4,4-diphenylheptan-3-one.

References Cited in the file of this patent UNITED STATES PATENTS 2,387,447 Hotfmann et al. Oct. 23, 1945 2,538,130 Sletzinger et al. Jan. 16, 1951 FOREIGN PATENTS 61,463 Denmark Oct. 11, 1943 OTHER REFERENCES Thorp et al.: Nature" (November 1, 1947), vol. 160, pp. 605-6.

Brockmuhl et al.: Annalen (1948), vol. 561, pp. 52-85. 

1. A MEMBER OF THE CLASS CONSISTING OF A FREE BASE AND ACID ADDITION SALTS THEREOF WITH NON-TOXIC ACIDS, SAID FREE BASE POSSESSING THE FORMULA 